Novel heteroaryl phosphonates as cardioprotective agents

Abstract

The invention teaches compound of general formula: Wherein: R 1 is selected from H and CH 3 , and R 2 is selected from H and OH, or R 1 and R 2 together form an optionally substituted phenyl ring which is fused to the pyridine ring; and R 3 is selected from H, CH 3 , CH 2 OH and R 4 is selected from H, CH 3 , CH 2 OH, R 5 is selected from H, phenyl, halogen-substituted phenyl and Wherein R 6 and R 7 are each independently selected from H, Na + , K + , alkyl and optionally substituted aryl, and X and Y are each independently selected from H, OH and F, or at least one of X and Y is an heteroatom and together with R 3 forms a bridge with the proviso that R 4 is and N-oxides thereof, and biologically acceptable salts thereof, related compounds, related pharmaceutical compositions, and methods for treating various disorders using such compositions.

We claim:  
     
         1 . A compound of general formula:  
       
         
           
           
               
               
           
         
       
       Wherein: 
 R 1  is selected from H and CH 3 , and R 2  is selected from H and OH, or R 1  and R 2  together form an optionally substituted phenyl ring which is fused to the pyridine ring; and  
 R 3  is selected from H, CH 3 , CH 2 OH and  
                     
 R 4  is selected from H, CH 3 , CH 2 OH,  
                     
 R 5  is selected from H, phenyl, halogen-substituted phenyl and  
                     
 Wherein R 6  and R 7  are each independently selected from H, Na + , K + , alkyl and optionally substituted aryl, and X and Y are each independently selected from H, OH and F, or at least one of X and Y is an heteroatom and together with R 3  forms a bridge with the proviso that R 4  is  
                     
 and N-oxides thereof, and biologically acceptable salts thereof.  
 
     
     
         2 . The compound according to  claim 1 , wherein said halogen-substituted phenyl is a fluoro-substituted phenyl.  
     
     
         3 . The compound according to  claim 1 , wherein said halogen-substituted phenyl is p-C 6 H 4 F.  
     
     
         4 . The compound according to  claim 1 , wherein said heteroatom is selected from O and S.  
     
     
         5 . The compound according to  claim 1 , wherein said heteroatom is O.  
     
     
         6 . The compound according to  claim 1 , wherein said bridge is selected from —CH 2 —, —CH 2 CH 2 — and —CH 2 CH 2 CH 2 —.  
     
     
         7 . The compound according to  claim 1 , wherein said bridge is a methylene bridge.  
     
     
         8 . The compound according to  claim 1 , wherein said alkyl is a C 1  to C 6  straight or branched alkyl.  
     
     
         9 . The compound according to  claim 1 , wherein said alkyl is t-butyl.  
     
     
         10 . The compound according to  claim 1 , wherein said aryl is phenyl or naphthyl.  
     
     
         11 . The compound according to  claim 1 , wherein R 1 , R 2 , R 4 , R 5  are all H and R 3  is  
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 1 , wherein R 1 , R 2 , R 3 , R 5  are all H and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 1 , wherein R 1 , R 2 , R 3 , R 4  are all H and R 5  is  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound according to  claim 1 , wherein R 1  and R 2  together form an optionally substituted phenyl ring which is fused to the pyridine ring; R 3  and R 5  are both H; and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 1 , wherein R 1  and R 3  are both CH 3 ; R 2  is OH; R 5  is H; and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound according to  claim 1 , wherein R 1  and R 4  are both CH 3 ; R 2  is OH; R 5  is H; and R 3  is  
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound according to  claim 1 , wherein R 1  is CH 3 ; R 2  is OH; R 3  is CH 2 OH; R 5  is H; and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound according to  claim 1 , wherein R 1  is CH 3 ; R 2  is OH; R 3  is CH 2 OH; R 5  is H; and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound according to  claim 1 , wherein R 1  is CH 3 ; R 2  is OH; R 3  is CH 2 OH; R 5  is C 6 H 5 ; and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , wherein R 1  is CH 3 ; R 2  is OH; R 3  is CH 2 OH; R 5  is p-C 6 H 4 F; and R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound according to  claim 1 , wherein R 5  is p-C 6 H 4 F.  
     
     
         22 . A compound according to  claim 1  selected from: [Hydroxy-(5-hydroxy-4-hydroxymethyl-6-methyl-2-phenyl-pyridin-3-yl)-methyl]-phosphonic acid; {[2-(4-Fluoro-phenyl)-5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-yl]-hydroxymethyl}-phosphonic acid; [Hydroxy-(4-pyridin-2-yl-phenyl)-methyl]-phosphonic acid; [Fluoro-(4-pyridin-2-yl-phenyl)-methyl]-phosphonic acid; (Hydroxy-quinolin-3-yl-methyl)-phosphonic acid; (Fluoro-quinolin-3-yl-methyl)-phosphonic acid; [Hydroxy-(5-hydroxy-4,6-dimethyl-pyridin-3-yl)-methyl]-phosphonic acid; (Hydroxy-pyridin-4-yl-methyl)-phosphonic acid; (Hydroxy-pyridin-3-yl-methyl)-phosphonic acid; (3,7-Dihydroxy-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-3-yl)-phosphonic acid; [(3,7-Dihydroxy-6-methyl-1,3-dihyrdo-furo[3,4-c]pyridin-3-yl)-difluoromethyl]-phosphonic acid; and nicotinyl phosphonates thereof, N-oxides thereof, phosphonate esters thereof and biologically acceptable salts thereof.  
     
     
         23 . A compound according to  claim 1  comprising:  
       
         
           
           
               
               
           
         
       
     
     
         24 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         25 . The compound according to  claim 1 , wherein at least one polar group is blocked by a lipophilic moiety capable of being enzymatically cleaved off after absorption into the circulatory system.  
     
     
         26 . The compound according to  claim 25 , wherein said lipophilic moiety is an ester.  
     
     
         27 . The compound according to  claim 25 , wherein said lipophilic moiety is a phosphonate ester.  
     
     
         28 . A method of treating hypertension in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         29 . A method of treating myocardial infraction in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         30 . A method of treating ischemia reperfusion injury in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         31 . A method of treating myocardial ischemia in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         32 . A method of treating congestive heart failure in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         33 . A method of treating arrhythmia in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         34 . A method of reducing blood clots in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         35 . A method of treating hypertrophy in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         36 . A method of treating a disease that arises from thrombotic and prothrombotic states in which the coagulation cascade is activated in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         37 . A method of treating diabetes mellitus in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to (a) in a unit dosage form.  
     
     
         38 . A method of treating insulin resistance in a mammal comprising concurrently administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         39 . A method of treating hyperinsulinemia in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         40 . A method of treating diabetes-induced hypertension in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         41 . A method of treating diabetes-related damage to blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin, connective tissue, or immune system in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         42 . A method of treating obesity in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to  claim 1  in a unit dosage form.  
     
     
         43 . A compound according to  claim 1  which is a nicotinic acid derivative.  
     
     
         44 . A kit comprising the composition of  claim 1  and instructions for its use in the treatment of a cardiovascular disease, a disease that arises from a thrombotic or prothombotic state in which the coagulation cascade is activated, diabetis, or related diseases.